HCLS/ParkinsonUseCase

Parkinson’s Disease Use Cases

Several views of Parkinson’s disease are outlined below. They address the same disease but at different levels of abstraction and under different agendas.

Systems Physiology View

A systems neurophysiology view of Parkinson’s disease focuses on a region of the brain known as the basal ganglia. The starring role in Parkinson’s disease is played by the basal ganglia structure known as the substantia nigra.

A part of the substantia nigra is composed neurons that transmit the chemical dopamine. It’s when these dopamine transmitting neurons in the substantia nigra die, that the amount of dopamine released into another part of the basal ganglia known as the striatum decreases and Parkinson’s disease symptoms appear.

The striatum connects to a third part of the basal ganglia known as the pallidum. In fact, there are two distinct connections that form parallel anatomical pathways from the striatum to the pallidum. One connection is known as the direct pathway and the other the indirect pathway. Each pathway is activated in a different way by the dopamine released from the substantia nigra. Activating the direct pathway facilitates movement, for instance moving your arm or legs. In contrast, activating the indirect pathway inhibits movement.

At the systems physiology level it is the balance of activity between the indirect and direct pathways from the striatum to the pallidum that at one extreme leads to Parkinson’s disease (over-activity in the indirect pathway results in over-inhibited, or not enough, movement D1 receptor) and at the other extreme leads to Huntington’s disease (over-activity in the direct pathway results in too much movement D2 receptor).

Systems neurophysiologists try to learn more about the normal functioning of these circuits and their malfunction in Parkinson’s disease by asking questions like:

What are the wiring diagrams of the brain systems?

Concepts of interest: Brain, System Model of Brain, Wiring Diagram of System Model of Brain

What chemicals (neurotransmitters) are used by each circuit element (neuron) to communicate with the next element (neuron)? What responses do they elicit in the neurons?

Concepts of interest: Chemical, Neurotransmitter (subtype of Chemical), Circuit Element of System Model of Brain, Neuron, Communicates With

What proteins (receptors) recognize those chemicals (neurotransmitters) and what are the responses that they elicit in the neuron?

What are the response properties of a particular kind of neuron in a particular part of the brain to particular input?

Concepts of interest: Properties of response, Part of Brain

What is the “neuronal code?” How is it transformed? What information does it contain?

Concepts of interest: Code of Neuron, Information contained in Code of Neuron, Transformed_To

Cellular and Molecular Biologist View

Studies identifying genes involved with Parkinson's disease are rapidly outpacing the cell biological studies which would reveal how these gene products are part of the disease process in Parkinson's disease. The alpha synuclein and Parkin genes are two examples.

The discovery that genetic mutations in the alpha synuclein gene could cause Parkinson's disease in families has opened new avenues of research in the Parkinson's disease field. When it was also discovered that synuclein was a major component of Lewy bodies, the pathological hallmark of Parkinson's disease in the brain, it became clear that synuclein may be important in the pathogenesis of sporadic Parkinson's disease as well as rare cases of familiar Parkinson's disease. More recently, further evidence for the intrinsic involvement of synuclein in Parkinson's disease pathogenesis was shown by the finding that the synuclein gene may be triplicated or duplicated in familiar Parkinson's disease, suggesting that simple overexpression of the wild type protein is sufficient to cause disease. Since the discovery of synuclein, studies of genetic linkages, specific genes, and their associated coded proteins are ongoing in the Parkinson's disease research field - transforming what had once been thought of as a purely environmental disease into one of the most complex multigenetic diseases of the brain.

Studies of genetic linkages, specific genes, and their associated coded proteins are ongoing in the Parkinson's disease research field. Mutations in the Parkin gene cause early onset Parkinson's disease, and the parkin protein has been identified as an E3 ligase, suggesting a role for the proteasomal pathway of protein degradation in Parkinson's disease. DJ-1 and PINK-1 are proteins related to mitochondrial function in neurons, providing an interesting genetic parallel to mitochondrial toxin studies that suggest disruptions in cellular energetics and oxidative metabolism are primarily responsible for Parkinson's disease. Other genes, such as UCHL-1, tau, and the glucocerebrosidase gene, may be genetic risk factors, and their potential role in the sporadic Parkinson's disease population remains unknown. Mutations in LRRK2, which encodes for a protein called dardarin, is the most recently discovered genetic cause of Parkinson's disease, and LRRK2 mutations are likely to be the largest cause of familial Parkinson's disease identified thus far. Dardarin is a large complex protein, which has a variety of structural moieties that could be participating in more than a dozen different cellular pathways in neurons. Because the cellular pathways that lead to Parkinson's disease are not fully understood, it is currently unknown, how, or if, any of these pathways intersect in Parkinson's disease pathogenesis.

Are there any potential biomarkers for Parkinson's disease based on these proteins?

Concepts of interest: Biomarkers of Disease, Protiens associated with Biomarkers of Disease

Clinical Researcher View

Clinical researchers, including both academic and commercial investigators, make use of knowledge generated by basic scientists in order to evaluate approaches to diagnosing and treating Parkinson’s disease that are superior to existing approaches.

Clinical researchers ask:

Can a certain diagnostic test (e.g., a blood test for a biomarker or an imaging study) provide an approach to diagnosing Parkinson’s disease that is superior to or can complement existing diagnostic approaches?

Can a certain therapeutic intervention (e.g., a drug targeted at a protein implicated in the pathogenesis of the disease) provide an approach to treating Parkinson’s disease that is superior to or can complement existing diagnostic approaches?

Clinical Guideline Formulator View

Academic researchers and professional societies synthesize the available evidence regarding the diagnosis and management of Parkinson’s disease to generate human-readable clinical guidelines. A similar process may also be used to formulate the content for clinical texts.

Clinical guideline formulators ask:

What have been the results of clinical trials that have evaluated the benefits and costs associated with diagnostic or therapeutic interventions for Parkinson’s disease?

Concepts of interest: Clinical Trial, Result of Clinical Trial, Benefit of Intervention, Intervention for Disease

How were these clinical trials conducted? For example, were they conducted as double-blind randomized controlled trials? What was the sample size? Was the trial adequately powered?

Concepts of interest: Type of clinical trial, Sample Size of Clinical Trial, Power of Clinical Trial

What recommendations can be made to clinicians based on the results of these clinical trials? How strong is the evidence for these recommendations?

Clinical Decision Support System Implementer View

Implementers of clinical decision support (CDS) systems (systems that make use of patient data to provide patient-specific assessments or recommendations to clinicians to assist with clinical decision making) encode knowledge regarding the diagnosis and/or treatment of Parkinson’s disease into a format that can be used to provide CDS. How the knowledge is represented depends on a number of factors, including: (1) the IT environment in which the CDS is to be provided; (2) the CDS execution architecture to be used; (3) whether the CDS system provides the advice to clinicians as part of their clinical workflow or responds to active requests from clinicians to provide advice; and (4) whether the CDS system can ask question to a human user to obtain the information necessary to provide the CDS.

CDS system implementers ask:

Is there a problem in how clinicians are currently diagnosis and/or treating Parkinson’s disease?

What information model should be used to represent the relevant data elements (e.g., symptoms, biomarkers, image results), and what terminologies (e.g., SNOMED CT, ICD9, LOINC) should be used to identify clinical concepts?

Concepts of interest: Metadata information related to the controlled terminology and information model used

Primary Care Clinician View

A primary care clinician would typically manage a patient with Parkinson’s disease in collaboration with a neurologist. A primary care clinician may be able to find the time to consult information resources, although the literature indicates that most clinical questions remain unanswered in routine clinical practice.

Primary care clinicians ask:

If a patient is not currently diagnosed with Parkinson’s disease, do the patient’s current symptoms indicate the need for further diagnostic evaluation within the primary care setting? If so, what further evaluation is required?

Concepts of interest: Patient, Patient diagnosed with Disease, Current Symptoms of Patient, Evaluation of Patient

If a patient is not currently diagnosed with Parkinson’s disease, do the patient’s current symptoms indicate the need for a referral to a neurologist for further evaluation? If so, what are the referral criteria? Concepts of interest: Referral for Patient, Referral Criteria for Patient

If a patient is currently diagnosed with Parkinson’s disease, does the patient have any symptoms or signs that indicate the patient’s current management plan for Parkinson’s disease (as formulated by a neurologist) is in need of change?

Concepts of interest: Management Plan for Patient

Neurologist View

Neurologists work with primary care clinicians to manage patients with Parkinson’s disease.

Neurologists ask:

What is the differential diagnosis for this patient given his/her symptoms, signs, and diagnostic test results?

Concepts of Interest: Differential Diagnosis for Patient

What diagnostic intervention is indicated next given the current state of knowledge regarding the patient?

What management plan is indicated for this patient?

What are the costs and benefits associated with each treatment option?

Concepts of interest: Cost of Therapy, Benefit of Therapy

What is the prognosis for this patient?

Concepts of interest: Prognosis for Patient

Is the current management plan optimal for the patient?

Questions

What genes are currently known or suspected to be implicated in Parkinson's Disease?

Which genes are involved in adult neurogenesis in particular involved in learning and memory in the hippocampus?

What brain regions, nuclei, and tracts are implicated in Parkinson's Disease?

What non-human models exist for Parkinson's Disease? (Last week I heard a talk by Leo Pallanck on fruit fly research on Parkinson's disease!)